Sex-related differences have been previously reported in the susceptibility and progression of alcohol use disorders, presence or absence of comorbid conditions, and treatment response. For example, alcohol consumption is higher and alcohol dependence is more common in males, whereas females are more likely to drink heavily when experiencing unpleasant emotions or in effort to relieve psychological distress. Our previous research suggests that genetic variation may contribute to these sex-related differences. Specifically, we have shown that variants in the PDYN gene increased risk for alcohol dependence in males, but increased the risk for negative (relief) craving in females. We have observed that sex-dependent effects of genetic variants are also phenotype-specific, suggesting complex relationships with endophenotypes, comorbidities, or other biological factors (such as sex hormones). However, the biological mechanisms underlying these genetic associations and other sex-specific differences in alcohol-related traits are not well understood. It is reasonable to suggest that differences in sex-related hormone levels across the sexes and/or genetic differences between the sexes may play an important role in these biological sex differences. Yet, there is a lack of systematic research addressing the impact of sex-related hormone levels on the risk of development of alcohol use disorders and no attempts to comprehensively investigate associations between alcoholism, sex-related hormone levels and genetic variation in male and female alcoholics. Importantly, our pilot study indicates that plasma levels of some of the sex-related hormones differ significantly between alcohol dependent cases and non-alcoholic controls. We hypothesize that both sex-related hormone levels and genetic factors are associated with sex differences in alcoholism and related traits. In a sample of 235 male and 118 female alcoholics matched to 235 male and 118 female non-alcoholic controls, we will 1) investigate the association between plasma levels of sex-related hormones (testosterone, estrogens, progesterone, LH, FSH and SHBG) and alcohol dependence; 2) investigate associations between plasma levels of sex-related hormones with alcoholism-related phenotypes, such as alcohol consumption, craving, withdrawal, comorbid depression and anxiety among alcohol-dependent males and females; and 3) examine the association between genetic variation and sex-related hormone levels in subjects with and without alcohol dependence. The findings of this study will lead to a better understanding of the biology of sex differences in alcohol use disorders, facilitating development of more effective and individualized treatment strategies.